CPN (Section Chief and Senior Investigator: Lorenzo Leggio, M.D., Ph.D., M.Sc.) Joint NIAAA-NIDA Annual Report 2019 The joint NIAAA-NIDA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN) conducts translational and clinical inpatient and outpatient studies to identify possible novel medications for addiction. Under the leadership of Lorenzo Leggio, M.D., Ph.D., M.Sc., the CPN team is particularly interested in the role of the gut-liver-brain axis in alcohol-seeking behaviors. Both preclinical and human approaches are in progress or under development to shed light on the possible role of the gut-liver-brain axis in alcohol and substance use disorders. Animal experiments demonstrate that central ghrelin administration not only stimulates reward processing but is also required for stimulation of that system by alcohol (Jerlhag et al., 2009; Suchankova et al., 2013). Human studies show a positive correlation between ghrelin concentrations and alcohol craving scores, and intravenous ghrelin acutely increases alcohol craving in individuals suffering with alcohol use disorder (AUD). Together, preclinical and clinical studies suggest that ghrelin might represent a novel pharmacological target for treatment (reviewed in: Zallar et al. 2017; Morris et al., 2018; Farokhnia et al., 2019). Contrary to animal studies, the hypothesis that GHS-R1a antagonism results in reduced alcohol use has never been tested in humans. To test this hypothesis, the CPN Section developed a translational project to assess the role of a GHS-R1a antagonist manufactured by Pfizer as a novel medication for AUD. This project was developed in collaboration with Fatemeh Akhlaghi, Pharm.D., Ph.D., from the University of Rhode Island and was recently awarded with a NCATS grant award (UH2/UH3 TR000963) to partially support this project. This study is conducted at the NIH Intramural Research Program under Dr. Leggios leadership; pharmacokinetics (PK)/pharmacodynamic (PD) investigations are conducted in Dr. Akhlaghis lab. A Phase 1b clinical study (protocol 14-AA-0042) was completed and recently published. The main results indicate that this GHS-R1a inverse agonist is safe and tolerable, when co-administered with alcohol and does not affect alcohol PK (Lee et al., Molecular Psychiatry in press). Very preliminary results also suggest that this compound reduces alcohol- and food-cue induced cravings in our bar-lab (Lee et al., Molecular Psychiatry in press). Furthermore, a secondary analysis from the same study indicates that this novel compound is safe on endocrine-related outcomes and its effects on some hormone levels suggest potential mechanisms requiring further investigation (Lee et al., Neuropharmacology in press). Furthermore, by using a r Reverse translational bed-to-bench approach, we recently discovered a major metabolite of this novel compound (Adusumalli et al., Drug Metab Dispos. 2019) and additional work on this metabolite is ongoing. A Phase 2a clinical study (protocol 16-AA-0080) is currently ongoing. We are continuing work on the effects of IV ghrelin on a variety of behavioral and neuroendocrine outcomes in AUD individuals. Consistent with the complex interplay between ghrelin, addiction and the HPA axis (which we reviewed in Morris et al., 2018), we recently reported that, compared to placebo, IV ghrelin leads to an increase in cortisol and aldosterone blood levels (Haass-Koffler et al., Neuropharmacology 2019). We have recently developed a novel GHS-R global knock-out rat model, in collaboration with PIs of the NIDA IRP (Drs. Brandon Harvey, Leandro Vendruscolo and George Koob). This model has been characterized from a histology, neuroendocrine and behavioral standpoint (Zallar et al., International Journal of Obesity 2019). Additional work using this KO rat model is ongoing and for example, we recently showed that GSHR KO rats consume less alcohol compared to the WT controls in a model of short-term binge drinking (Zallar et al., Journal of Neuroendocrinology 2019). Increasing evidence suggests a role of the gut microbiota in neuropsychiatric disorders. Clinical and translational research has suggested a causality link between the gut microbiota and symptoms of anxiety, depression and autism (reviewed in: Dinan and Cryan, 2016). A recent study suggests that changes in the gut microbiota in patients with AUD and increased gut permeability correlate with alcohol craving. However, the small sample size and the retrospective and self-reported nature of some of the assessments limit the interpretation of these findings. A recent systematic review conducted by our team, (Temko et al., Alcohol and Alcoholism 2017) indicates that the understanding of the role of the gut microbiota in AUD is very limited and deserves additional investigation. Therefore, the CPN Section developed a translational and clinical project to investigate the role of the gut microbiota in AUD. Dr. Leggio received a grant award from the Peter G. Dodge Foundation to partially support this study. This clinical study (17-AA-0093) and preclinical experiments are currently ongoing. Finally, additional projects have been completed: 1) we are continuing work on oxytocin. For example, in collaboration with Dr. Tanda (NIDA IRP), we recently completed a study on the effect of systemically administered oxytocin on dose response for methylphenidate self-administration and mesolimbic dopamine levels (Lee et al., Ann N Y Acad Sci. 2019); in collaboration with Drs Barb and McQuenn (NIH CIT), we applied machine learning to classify individuals with alcohol use disorder based on treatment seeking status (Lee et al., EClinicalMedicine. 2019); we recently completed a meta-analysis on the role of dopamine D4 receptor gene (DRD4) on alcohol-related phenotypes (Daurio et al., Addict Biol. 2019); and we contributed a played a senior leadership role in the development of an international consensus statement on the role of the GABA-B receptor agonist baclofen in AUD (Agabio et al., Lancet Psychiatry 2019).